Approximately 15% of newly diagnosed cases of ALL in adults are T cell ALL (T-ALL). Current treatments result in complete remission in 80% - 90%, but the 5-year survival is less than 30%. The outcome of relapsing patients is very poor with 5-year survival of approximately 5%. Early T-cell precursor ALL (ETP-ALL) comprises up to 15% of T-ALL and is associated with particularly high risk of treatment failure. Therefore, it is imperative to generate new therapies that alone or in combination with traditional treatments could potentially extend the complete remission time and/or be used in the refractory T-ALL patients. T-ALL may accumulate spontaneous potentially lethal DNA double-strand breaks (DSBs) caused by reactive oxygen species (ROS) and recombination-activating genes 1 and 2 (RAG1/2) in ATM-deficient T- ALLs. In addition, one of the goals of intensive therapies is to induce DSBs in T-ALL cells. Thus, T-ALL cells may be addicted to DSB repair mechanisms to survive genotoxic stress. Targeting these pathways could sensitize T-ALL to the lethal effect of DNA damage. In proliferating cells DSBs result from broken replication forks and their repair usually depends on BRCA1/PALB2/BRCA2 -dependent RAD51-mediated homologous recombination repair (HRR). Wide-range expression levels of BRCA1, PALB2 and BRCA2 were detected in T-ALL and ETP-ALL patients; approximately 35-50% of T-ALL and >90% of ETP-ALL displayed BRCA-deficient (no/low expression of at least one of these genes) phenotype. In the BRCA-deficient cells alternative mechanisms of HRR such as RAD52-RAD51 may emerge to protect cells from the lethal effect of DSBs. To attack RAD52 we designed small peptide aptamer mimicking RAD52 region surrounding phenylalanine 79 (F79). Aptamer F79 disrupted RAD52-DNA binding and inhibited HRR resulting in accumulation of toxic DSBs and synthetic lethality in experimental murine leukemia cells displaying BRCA-deficient phenotype. Moreover, F79 aptamer eradicated BRCA-deficient leukemia in SCID mice. Normal cells and tissues were not affected by the aptamer. Our preliminary data indicate that T-ALL cells obtained from primary leukemia xenografts (PLXs) displaying BRCA-deficient phenotype are highly sensitive to F79 aptamer, conversely T-ALL cells harvested from BRCA-proficient PLXs were resistant to the aptamer. Thus, we hypothesize that inhibition of RAD52 activity will induce synthetic lethality in BRCA-deficient T-ALL/ETP-ALL. In Aim #1 using qRT-PCR, microarrays, and flow cytometry we will identify T-ALLETP/ALL primary cells expressing low/high levels of proteins in BRCA pathway. Then BRCAlow (BRCA-deficient) and BRCAhigh (BRCA-proficient) cells will be treated in vitro with F79 peptide aptamer alone or in combination with already approved treatment modalities. We expect that: (a) F79 aptamer will induce apoptosis in BRCA-deficient but not in BRCA-proficient T-ALL/ETP-ALL cells, and/or (b) F79 will exert synergistic effect with already approved therapies only in BRCA-deficient T-ALL/ETP-ALL cells. In Aim #2 NSG mice bearing BRCA-deficient or BRCA-proficient T-ALL/ETP-ALL PLXs will be treated with F79 aptamer and/or standard therapy. We expect that the aptamer either alone or in combination with standard therapeutics will exert anti-leukemia activity in vivo in BRCA-deficient PLXs.